Micronutrients, Birth Weight, and Survival

NU30CH05-Christian ARI 7 July 2010 2:53

Micronutrients, Birth Weight,and SurvivalParul ChristianCenter for Human Nutrition, Department of International Health, Johns HopkinsBloomberg School of Public Health, Baltimore, Maryland 21205; email: [email protected]

Annu. Rev. Nutr. 2010. 30:83–104

First published online as a Review in Advance onApril 23, 2010

The Annual Review of Nutrition is online atnutr.annualreviews.org

This article’s doi:10.1146/annurev.nutr.012809.104813

Copyright c© 2010 by Annual Reviews.All rights reserved

0199-9885/10/0821-0083$20.00

Key Words

pregnancy, maternal, infant, fetal growth, mortality, gestation,vitamins, minerals

Abstract

Maternal micronutrient requirements during pregnancy increase tomeet the physiologic changes in gestation and fetal demands for growthand development. Maternal micronutrient deficiencies are high and co-exist in many settings, likely influencing birth and newborn outcomes.The only recommendation for pregnancy currently exists for iron andfolic acid use. Evidence is convincing that maternal iron supplementa-tion will improve birth weight and perhaps gestational length. In onerandomized trial, iron supplementation during pregnancy reduced childmortality in the offspring compared with the control group. Few othersingle micronutrients given antenatally, including vitamin A, zinc, andfolic acid, have been systematically shown to confer such a benefit. Ameta-analysis of 12 trials of multiple micronutrient supplementationcompared with iron-folic acid reveals an overall 11% reduction in lowbirth weight but no effect on preterm birth and perinatal or neonatalsurvival. Currently, data are unconvincing for replacing supplementa-tion of antenatal iron-folic acid with multiple micronutrients.

83

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


Low birth weight(LBW): weight lessthan 2500 g at birth

FGR: fetal growthrestriction

Preterm birth: birthat <37 weeks ofgestation

Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 84MATERNAL

MICRONUTRIENTDEFICIENCIES INPREGNANCY: BURDENAND CAUSES . . . . . . . . . . . . . . . . . 85

MECHANISMS AND PATHWAYSBY WHICHMICRONUTRIENTS MAYINFLUENCE FETAL GROWTHAND GESTATIONALDURATION . . . . . . . . . . . . . . . . . . . . . . 86Epigenetic Factors

and Gene Imprinting. . . . . . . . . . . . 86Plasma Volume Expansion . . . . . . . . . 87Placental Factors . . . . . . . . . . . . . . . . . . . 87Endocrine Factors . . . . . . . . . . . . . . . . . 88Fetal Hypothalamic Pituitary

Adrenal Axis . . . . . . . . . . . . . . . . . . . . 88Maternal Nutrient Status and

Transfer . . . . . . . . . . . . . . . . . . . . . . . . 88SUMMARY OF THE IMPACT OF

SINGLE MICRONUTRIENTSON BIRTH WEIGHT ANDINFANT MORTALITY . . . . . . . . . . 89

SUMMARY OF THE IMPACT OFMULTIPLE-MICRONUTRIENTSUPPLEMENTATION TRIALSON BIRTH WEIGHT ANDINFANT MORTALITY . . . . . . . . . . 91

INTERPRETATION OF RESULTS,PLAUSIBLE MECHANISMS,AND NUTRIENTINTERACTIONS . . . . . . . . . . . . . . . . 96

SUMMARY AND CONCLUSION. . . 98

INTRODUCTION

Low birth weight (LBW; <2500 g) continues tobe a major public health problem worldwide, af-fecting the immediate and long-term health andsurvival of offspring in both developed and de-veloping countries. Although infant and under-five mortality rates have been slowly declining,the prevalence of LBW remains steady and may

perhaps be increasing in some populations (60,106). The global prevalence of LBW is esti-mated at ∼15% but may be higher (∼30% orgreater) in parts of South Asia. The short-termconsequences of LBW are well known and in-clude increased perinatal and infant mortality,poor postnatal growth, and impaired immunefunction (65). The relationship between birthweight and infant mortality is inverse and linear,except at the higher tail of the birth weight dis-tribution. Between the two biologic processesthat underlie low birth weight—fetal growthrestriction (FGR) and preterm birth—the lattermay carry a higher risk of mortality (18). Themajority of infants with FGR are born in devel-oping countries, with the highest rates observedin South Asia and sub-Saharan Africa (106).Since birth weight does not capture differencesin gestational age, classification of newborns ac-cording to their size-for-gestational age is of-ten used to identify FGR. For example, smallfor gestational age (SGA) is defined as <tenthpercentile of weight in a reference populationat the same gestational age. A single cut-off of<2500 g to define LBW has been in questionas maternal size (height), sex of the offspring,and other biologic factors may be importantin determining the optimal size at birth (38).Birth weight, however, despite being a proxyand crude measure of newborn health, remainsthe most convenient measurement to take andwill continue to be utilized both clinically andas a global indicator of health.

More than two decades ago, Kramer (59)showed that maternal nutritional factors mayaccount for more than 50% of the etiology ofLBW in developing countries. These factors in-cluded low prepregnancy weight, short stature,and low caloric intake during pregnancy (orweight gain) as well as maternal LBW. Notcoincidentally, rates of LBW are high in set-tings where maternal malnutrition is common.Physiologic changes and increased metabolicdemands to meet fetal requirements for growthand development make gestation a critical, nu-tritionally responsive period of life for bothmother and fetus. On the basis of 13 random-ized controlled trials, balanced energy-protein

84 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


supplementation in pregnancy has been shownto reduce FGR by 32% (20% to 43%) (61,68) but has shown only modest, nonsignificanteffects of 37.6 g (−0.21, 75.45) on mean in-crements in birth weight (61). These resultsdemonstrate limited benefit of macronutrientson infant growth and have generated interestin the potential role of essential micronutrients(vitamins and minerals) for assuring adequatefetal growth and health. Given the multitude offunctions of micronutrients, especially in pro-tein and energy metabolism, it is plausible thatcertain individual or combinations of micronu-trients may limit the effectiveness of macronu-trients in enhancing birth size.

A further motivation for enhancing birthsize stems from research advances in the areaof developmental origins of health and disease,which have now well demonstrated that loweror suboptimal birth weight may contribute tocoronary heart disease, stroke, hypertension,and type 2 diabetes through fetal programmingthat makes individuals more susceptible to en-vironments of excess later in life (5). Fetal de-velopment is a period of plasticity, which allowsfor the phenotype to respond to environmentalcues such as energy (and potentially micronu-trient) restriction (40, 112). Therefore, improv-ing birth weight through micronutrient inter-ventions may confer both short- and long-termbenefits for the offspring.

This review examines the evidence for thecontribution of micronutrient deficiencies infetal growth, gestational length, and infantmortality, focusing on the literature amongnon-HIV-1 populations.

MATERNAL MICRONUTRIENTDEFICIENCIES IN PREGNANCY:BURDEN AND CAUSES

Multiple, not single, micronutrient deficienciesare likely to affect women of reproductive age,especially during pregnancy. Micronutrient de-ficiencies in pregnant women continue to bea major public health problem in low-incomecountries for a variety of reasons. These in-clude poor access to a nutrient-adequate diet

Small for gestationalage (SGA): birthweight less than thetenth percentile ofweight for a givengestational age in areference population

due to low income, bioavailability, and sea-sonality; increases in metabolic and physio-logic demands of pregnancy; cultural practices;and infections. Micronutrients are essential forgrowth, metabolism, and cell differentiation,but only a few specific nutrients have receivedappreciable study in human pregnancy (12, 32).The global prevalence of maternal vitamin Adeficiency is estimated to be 18.4% using serumor breast milk vitamin A concentrations of<1.05 μmol/L; it is estimated to be 5.8% usingthe indicator of night blindness during preg-nancy (111). The global prevalence of anemiaamong pregnant women is estimated at 42%(27), with approximately half of the anemia at-tributable to iron deficiency.

Multiple, concurrent deficiencies when ex-amined in a few populations are seen in highproportions (50, 80). For example, in Nepal,multiple deficiencies coexisted in early ges-tation, when the impact of hemodilution onserum concentrations was minimal (Figure 1).Prevalence rates of low serum concentra-tions were high for zinc, iron, and B-complexand other vitamins, with more than 80% ofwomen experiencing at least two micronu-trient deficiencies (50). Similarly, a surveyfrom a rural area of Haryana State of Indiafound deficiencies to be concurrent in late preg-nancy, especially those of iron and zinc (80).Dietary intake data collected as part of thisstudy also found that 75%–100% of womenwere consuming less than the recommendeddaily allowance (RDA) for folic acid, zinc,iron, copper, and magnesium. In rural Shaanxi,China, semiquantitative food frequency ques-tionnaire data revealed inadequate intakes offolate (97%), zinc (91%), and iron (64%) inpregnant women (17). In peri-urban Mexico,prevalence of zinc and folate deficiency in thethird trimester was 34% and 19%, respec-tively, and that of low vitamin A status was17.6% among women in the control group of amicronutrient trial (37). Despite some dataavailable to demonstrate widespread micronu-trient deficiency in pregnancy, few representa-tive studies have examined the status of a widerrange of micronutrients.

www.annualreviews.org • Micronutrients, Birth Weight, and Survival 85

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


MECHANISMS AND PATHWAYSBY WHICH MICRONUTRIENTSMAY INFLUENCE FETALGROWTH AND GESTATIONALDURATION

Fetal growth is a complex process influencedthroughout gestation by the maternal environ-ment, both nutritional and health, and geneticendowment and the interaction between thetwo. These pathways and the influence ofmicronutrients are not well understood in hu-mans. Although peak gains in fetal length occurduring the second trimester, gains in weight aregreatest in the third trimester, as fat and muscleand pools of nutrient stores are deposited toa large extent in the final stages of pregnancy(109). Birth weight is the summary measureof the interactions between these factors in alive born infant, and a given size at birth mayresult from a wide variation in intrauterinegrowth trajectory and body dimension andcomposition; at a given birth weight, organsize, development, and maturity may vary(45). Among the many aspects of the dynamicmaterno-placento-fetal environment, several

are believed to exert a particular influence onbirth and postnatal outcomes, including theefficiency and adequacy of maternal plasmavolume expansion, placental endocrine factors,hormonal balance and metabolism within thefetus, and materno-fetal nutrient transfer.Gene imprinting and epigenetic mechanismsalso play a role in early embryonic life andperhaps even prior to and during implantation.To what extent micronutrients may influencefetal growth and gestational age through thesepathways is elucidated below, with the caveatthat limited data are available from humanstudies (Figure 2).

Epigenetic Factorsand Gene Imprinting

In humans and other mammals, imprintedgenes—a class of genes found in the placentaand fetal tissues—appear to have a critical rolein feto-placental development. Genomic im-printing is the expression of a single allele of agene of maternal or paternal origin. Reik et al.(89) proposed that imprinted genes in the pla-centa control the supply of nutrients, whereas

Maternal micronutrient

status, supplementation

Birth Weight: Fetal Growth,

Gestational Age

Imprinted genes

Plasma volume expansion

Fetal HPA axes: maternal and fetal stress hormones

Endocrine factors controlling embryonic and

fetal growth: IGF-1, IGF-2, GH-2, hPL

Placental growth, morphology, and vascularization

Nutrient transfer to the fetus

Figure 2Conceptual framework for the pathways linking maternal micronutrient status and birth weight. GH-2,growth hormone 2; hPL, human placental lactogen; IGF, insulin-like growth factor.

86 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


in the fetal compartment they control nutrientdemand by regulating fetal growth. The actionof imprinted genes in regulating nutrient trans-fer involves the growth and transport capacityof the placenta and the modulation of nutri-ent requirements by the fetus, mainly throughthe control of fetal growth (89). Imprinting iscontrolled epigenetically by differential DNAmethylation, which in turn can be influencedby environmental factors including nutrition.In particular the reciprocally imprinted Igf2-H19 gene complex (H19 is the silent pater-nal allele) may play a central role in match-ing the placental nutrient supply to the fetalnutrient demands for growth (34). Gene im-printing is also one of the early factors affect-ing placental growth, vasculature, and trans-port capacity (34). Availability of methyl donorssuch as vitamin B12, folic acid, and some aminoacids during pregnancy has been found to al-ter DNA methylation in experiments in mice(110, 112), although the implications of thesemechanistic experiments to humans are not wellunderstood.

Plasma Volume Expansion

One of the earliest adaptations that occurs inpregnancy involves the expansion of blood vol-ume and related hemodynamic changes that arethe key to facilitating growth. The expansion ofmaternal plasma volume increases uterine andplacental blood flow, which in turn allows foradequate transport of nutrients and oxygen tothe fetus (29). Plasma volume increases progres-sively by about 1250 mL from 6 weeks untilabout 34 weeks gestation (10, 49). Red cell massalso increases, but to a lesser extent, and it lagsbehind, resulting in the physiologic anemia ofpregnancy. Inadequate plasma volume expan-sion is associated with preeclampsia and fetalgrowth restriction (96, 97, 108), and womenwho are underweight have a higher risk of poorplasma volume expansion and resulting poorfetal growth (95). In general, however, our un-derstanding of other factors influencing thisphysiologic change is inadequate. One clinicalimplication of this change is that high nutrient

concentration during pregnancy may reflecteither adequate nutritional status or poorexpansion.

Placental Factors

Placental growth, vascularization, and functionis also key for nutrient transfer and, ultimately,optimal fetal growth and weight at birth (88,94). The capacity to exchange nutrients ispartially dependent on vascularization of theplacenta, which in turn affects uterine and um-bilical blood flow (88). Women with growth-restricted fetus exhibit smaller placentas andreduced uterine blood flow (76). In terms ofweight, the majority of placental growth iscompleted by the end of the second trimester(88), and placental volume is then strongly cor-related with fetal weight (13, 56, 103). Maternalprepregnancy weight and weight gain earlyin pregnancy also influence placental volume(56, 102).

There is some evidence that maternalmicronutrient intake will improve placentalgrowth. In a study in Pune, India, higher pla-cental weight in women was associated witheating more micronutrient-rich foods (greenleafy vegetables, fruits, or milk products) (87),whereas in a large, randomized trial of multi-ple micronutrient supplementation, significantbut small (9 g, 95% CI: 4–14 g) increases inplacental weight at birth were observed amongthe intervention versus control subjects, albeitwomen were at ∼21 weeks gestation when sup-plementation commenced (33).

Angiogenesis, the formation of new bloodvessels from existing ones, is a process essentialfor the vascularization of the placenta (1, 91).Proper angiogenesis is associated with uterineand umbilical blood flow and therefore placen-tal growth and transfer nutrients (90). Severalfactors and their receptors have been identifiedin angiogenesis, including vascular endothelialgrowth factor (VEGF), placental growth factor(PlGF), basic fibroblast growth factor-2 (FGF-2), soluble VEGFR-1, and angiopoietin (1), butit is unclear whether micronutrients can in-fluence their expression or function. Placental


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


synthesis of nitric oxide—a major vasodilatorand angiogenesis factor—may be impaired withmaternal undernutrition in pigs, thus leadingto inadequate fetal growth (113), but such evi-dence is needed in humans.

Endocrine Factors

There is a strong connection between the en-docrine axes and fetal somatotrophic growth(39, 73). The dominant fetal growth regulatorin later gestation is insulin-like growth factor1 (IGF-1), produced by the fetal liver and tis-sues in response to glucose concentrations (75),and changes in IGF-1 may also reflect proteinmetabolism (104). The fetal IGF-1 system issensitive to maternal nutritional status as shownin animal studies (41). For example, in sheep,short-term maternal undernutrition leads to re-duced IGF-1 and altered IGF-1 binding pro-teins (6). There are no published studies link-ing maternal micronutrient status with theseendocrine factors controlling fetal growth inhumans.

Placental growth hormone or GH2 alsoplays several roles, including trophoblastinvasion, but its key role is somatotrophic(36). Additionally, GH-2 directly affectsplacental development and function, andits concentrations are decreased in mothersof infants with FGR (70). GH-2 is highlycorrelated with IGF-1, which is the proposedmechanism for its influence on growth (16,66) and also stimulates maternal anabolism,presumably to mobilize nutrients for transferto the fetus (4). Although a direct associationto micronutrient status has not been identified,there is a link between glucose concentrationsand secretion of GH-2 (4). Human placentallactogen (hPL) along with GH-2 are believedto create peripheral insulin resistance in themother that allows preferential glucose supplyto the fetus (41). In sheep, periconceptional,but not later, undernutrition results in alteredhPL production and premature activation ofthe hypothalamic pituitary adrenal (HPA) axis,resulting in premature delivery (see below).

Fetal Hypothalamic PituitaryAdrenal Axis

Fetal exposure to exogenous glucocorticoidsis known to impair fetal growth in animals(9), and increased levels have been observedin response to maternal protein malnutri-tion and poor placental function and bloodflow (42, 67). The placental enzyme 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2) is a crucial barrier, protecting the fetusfrom high maternal concentrations of corti-sol by inactivating it to cortisone (9). Mater-nal levels of cortisol are 5–10 times higherthan levels in the fetus, and when the placentais functioning normally, the majority of ma-ternal cortisol is converted to cortisone be-fore crossing (72). Late in gestation, the fetaladrenal gland secretes cortisol, and near term,75% of circulating cortisol is of fetal origin,whereas cortisone is mostly from the mother(8). Retinoic acid has been shown to stimulateproduction of 11β-HSD2 through mRNA ex-pression (105). Maternal anemia (causing hy-poxia) and iron deficiency may induce stressas well as elevated corticotropin-releasing hor-mone, which is known to increase the risk ofpreterm labor in animals (3). Corticotropin-releasing hormone also has a role in placen-tal vasodilation through regulation of nitric ox-ide, a relationship impaired in preeclampsia(52). Few other micronutrient deficiencies havebeen examined for their role in inducing fetalstress.

Maternal Nutrient Status and Transfer

Many micronutrient requirements increaseduring pregnancy to meet the nutrient supplyto the fetus. A complex relationship exists be-tween maternal nutrient intake (i.e., diet) andfetal nutrient uptake (32). Partitioning of nutri-ents in pregnancy is controlled by homeorheticmechanisms (7) such that if nutrients are lim-ited, the placenta and fetus receive priority overmost other maternal tissues when nutritionalstatus is adequate or mildly lacking (88). Thisstrategy is reversed when maternal deficiency is

88 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


severe, in which case the health and survival ofthe maternal organism is preserved (57).

There is much lacking in our understandingof nutrient transfer to the fetus. Micronutri-ents are often transferred to the fetus againstthe concentration gradient (e.g., iron and zinc),but not always (e.g., vitamins A and E). Corre-lations between maternal and cord blood levelshave been observed for some nutrients, includ-ing vitamin E, B12, and folate (55, 62), but towhat extent this impacts fetal size is not wellunderstood. A trial of zinc supplementation inPeru found higher zinc concentrations in ma-ternal and cord serum from treatment but noimprovement in birth weight (14). Lower lev-els of folate, riboflavin, vitamin A, and vita-min E in the cord blood have been associatedwith FGR/SGA (62, 74), but causality cannotbe attributed. For instance, in FGR, the normalrelationship between maternal and fetal levelsmay be altered (presumably from poor placen-tal function) (62). In one study among Pakistaniwomen, much lower concentrations of folatewere found in the cord blood of FGR versusnormal-weight infants, and fetal folate corre-lated with maternal levels (r = 0.63, p < 0.01)in normal-weight infants but not in FGR in-fants (r = 0.0), implying placental dysfunctionand abnormal nutrient transfer (62).

Observational studies conducted in Indianand Danish women have shown that womenwho eat more micronutrient-rich fruits andvegetables during pregnancy deliver infantswith higher birth weights (69, 87), but causalinference is lacking.

SUMMARY OF THE IMPACTOF SINGLE MICRONUTRIENTSON BIRTH WEIGHT ANDINFANT MORTALITY

Few vitamins and minerals when providedsingly during the fetal period via maternal sup-plementation seem to show consistent benefitson birth outcomes, including birth weight andinfant survival (28, 32, 68, 85). An exceptionto this may be iron, for which the strongestevidence for a beneficial effect has now been

accumulated via findings of several random-ized controlled trials. Two of these were well-designed trials done in the United States amongnonanemic, iron-sufficient women at enroll-ment. In these trials, supplementation duringpregnancy with iron compared to a placebosignificantly increased birth weight (by 100 to200 g) (27, 100). Further, iron supplementationreduced the incidence of low birth weight inboth studies, gestational age in one study (27),and preterm in the other (100). In a cluster-randomized controlled trial in Nepal, antenataliron-folic acid supplementation (but not folicacid alone) significantly reduced the incidenceof low birth weight by 16% (21), although thesmall reduction of ∼20% in three-month infantmortality was not significant (26). Recently, ina follow-up study in this trial, child mortalityfrom birth to 7 years of age was found to be sig-nificantly reduced by 31% (hazards ratio: 0.69,95% CI: 0.49, 0.99) in the offspring of motherswho had received iron-folic acid during preg-nancy relative to the controls (25), revealingfor the first time the benefit to child survivalof antenatal iron supplementation in an iron-deficient setting.

In a trial in China, maternal supplementa-tion with iron-folic acid compared with folicacid alone used as the control significantly re-duced early preterm (<34 wk) delivery (relativerisk = 0.50, 95% CI: 0.27, 0.94) and neona-tal mortality (RR = 0.53, 95% CI: 0.29, 0.97),although the impact on birth weight was notsignificant (115).

A recent Cochrane meta-analysis of antena-tal iron-folic acid supplementation found a 36 g(−5, 77 g) increase in mean birth weight, a 21%reduction in LBW (RR = 0.79, 95% CI: 0.61,1.03), and a 15% reduction in preterm birth(RR = 0.85, 95% CI: 0.67, 1.09) (81). Althoughall three treatment effects were nonsignificant,the point estimates are suggestive of a beneficialimpact. One concern with the analysis is that itincludes several extremely small studies of sam-ple sizes <20 per group that showed 100–300 glower weight in the iron-folic acid group com-pared with the control and does not include therecent study from China (115).


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


Since antenatal iron supplementation is al-ready a policy in many countries, it is relevantto show that iron use is beneficial for enhanc-ing birth outcomes in a programmatic context.This was recently demonstrated in Zimbabwewith data from the national Demographic andHealth Survey (DHS). Iron use during preg-nancy in this study was found to be associ-ated with a mean 103 g (42, 164 g) increase inbirth weight adjusted for confounding variables(71).

Findings with regard to the contribution ofother micronutrient deficiencies to birth out-comes are limited, and evidence for any ben-eficial effects is patchy. Folic acid is often in-cluded in iron supplements for antenatal use,but on its own does not seem to confer a bene-fit for birth weight or gestational duration (21,68). Thus, when iron and folic acid are com-bined, any benefit to hematologic status, birthweight, and preterm can safely be attributedto iron alone. Antenatal vitamin A supplemen-tation has also been found to show no im-pact on either birth weight or infant mortality(30, 54).

Zinc supplementation trials have foundlittle benefit of maternal supplementation dur-ing pregnancy on birth outcomes or maternalhealth (77). A recent Cochrane meta-analysiscombining 13 randomized controlled trialsshowed a small but significant reduction inpreterm delivery associated with zinc supple-mentation (RR = 0.86, 95% CI: 0.76, 0.98),although no similar reduction was observed inthe rates of LBW or other neonatal or maternaloutcomes (63). The authors concluded thatthe reduction in preterm delivery could bereflective of poor nutrition in general and thatzinc supplementation during pregnancy wouldnot be recommended based on these results.This may be prudent, as in some studies addingzinc to the currently recommended antenataliron-folic acid supplement has attenuated theefficacy of iron on birth weight and infant mor-tality outcomes (21, 26). On the other hand,in a recent review of zinc supplementation

during pregnancy, the addition of zinc to iron-folic acid is recommended for consideration,but more definitive research is called for todemonstrate an additive benefit (47).

A promising trace element for enhancingbirth weight may be magnesium, but it hasreceived little attention as an intervention forpregnancy. A meta-analysis of magnesium tri-als suggests a reduction in low birth weight andSGA of about 30%; however, all but one trialincluded in the meta-analysis were from devel-oped countries (68). Only observational stud-ies are available to examine the role of mater-nal vitamin D status, which is not consistentlyassociated with birth weight (32, 58, 82). Ma-ternal adaptations during pregnancy may partlybe an explanation, as total 1,25(OH)D concen-trations double or triple in maternal circulationbeginning in gestation, which can influence cal-cium absorption (58). Limited data from trialsexist for the role of other vitamins, including vi-tamins E and C, and B-complex vitamins, whichare required cofactors for energy metabolism(32, 85).

In summary, beyond iron, the evidencefor other micronutrients for enhancing birthweight and gestational length, although bio-logically plausible and supported by observa-tional studies and animal experimentation, isweak. For some nutrients, such as folate, vi-tamin A, and perhaps zinc, trial data are ad-equate and reveal no evidence for a benefit,whereas for others, such as magnesium and vi-tamin D, more research may be needed. Formany micronutrients, such as B-complex vi-tamins, vitamins D, C, E, and others, thereis a lack of sufficient data demonstrating theburden of deficiencies, especially in develop-ing countries, where these micronutrients arelikely to be limiting and may influence birthoutcomes. However, it is probably unlikely thatlarge, rigorous trials of single nutrients will beundertaken considering the momentum towardmultiple-micronutrient intervention strategiesfor pregnant women in developing countries(see below).

90 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


SUMMARY OF THE IMPACT OFMULTIPLE-MICRONUTRIENTSUPPLEMENTATION TRIALSON BIRTH WEIGHT ANDINFANT MORTALITY

In developed countries, women routinely usea one-a-day prenatal multivitamin and mineralsupplement during pregnancy. However, fewcontrolled clinical trials are available from de-veloped countries demonstrating the beneficialimpact, if any, of such supplement use on out-comes such as birth weight, length of gestation,and infant and maternal morbidity and mortal-ity. An older systematic review of 17 trials ofiron and vitamins exists, showing that beyondsome modest benefits of reduced preeclampsiaand fewer deliveries before the fortieth week inone to two studies, none of the studies reportedany benefit for other outcomes (46). Notably,most studies were identified to have method-ological and reporting errors and suffered fromlow sample sizes. The practice of prenatal vi-tamin and mineral supplement use, which isubiquitous in high-income countries, remainsrare among the poor of the developing world,where the burden of micronutrient deficienciesand poor birth outcomes is high and antenatalcare is poor. It stands to reason that mothers andinfants in this region may respond favorably toreductions in materno-fetal micronutrient de-ficiencies through antenatal supplementation.And yet, the full health benefits and safety ofsupplying prenatal multiple micronutrients, es-pecially across different high-risk populations,are not fully elucidated.

In recognition of this and of the needto test the efficacy of a single formulationof a multiple-micronutrient supplement foruse during pregnancy in developing countries,United Nations Children’s Fund (UNICEF),United Nations University, and the WorldHealth Organization (WHO) convened a tech-nical meeting in 1998 to discuss and proposea formulation of such a prenatal micronutri-ent supplement. Thus, the supplement (calledUNIMMAP, for United Nations Interna-tional Multiple Micronutrient Preparation) was

MMS: multiple-micronutrientsupplementation

created, containing 15 micronutrients atdosages that approximated the RDAs for preg-nancy (107). Over the past decade or so,12 randomized controlled trials of multiple-micronutrient supplementation (MMS) havebeen undertaken to examine, in most cases,the additional benefit of MMS over iron-folicacid alone (usually standard of care or pol-icy) in improving birth weight and other birthoutcomes. Many of these studies were coordi-nated by UNICEF, although some investiga-tors tested formulations slightly different fromthe UNIMMAP. These trials were conductedin developing countries—in South Asia, Africa,and Latin America—among largely non-HIVwomen who were supplemented daily fromearly to mid pregnancy through three monthspostpartum in most studies. Although perina-tal and neonatal mortality were assessed in sev-eral trials, few studies were powered to examinetreatment effects on mortality as an outcome.This section summarizes the findings of thesetrials and the results of three meta-analysesthat have been conducted using data from thesetrials.

Table 1 summarizes the study design, pop-ulations, and main results from the publishedtrials. In one of the first trials in Mexico, wherewomen were randomized to receive either iron(60 mg) or MMS containing the same amountof iron plus 11 other nutrients, there was no dif-ference in the mean birth weight and gestationalage between the two groups (83). MMS was as-sociated with increased weight retention dur-ing the postpartum period among overweightwomen, whereas the nonoverweight womenlost weight (84). A study in Zimbabwe thatincluded both HIV-1-infected and uninfectedpregnant women found a small increase in birthweight due to MMS versus placebo (49 g; −6,104 g), but it found no reduction in LBW (35).The treatment effect differed by maternal HIVstatus; 26 g (−38, 9 g) in HIV-negative womencompared with 101 g (−3, 205 g) among HIV-positive women (35). In this study, all womenreceived 60 mg of iron and 400 μg of folic acidseparately as per the national policy. A trial in


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


Tab

le1

Mat

erna

lmul

tipl

em

icro

nutr

ient

supp

lem

enta

tion

effe

cts

onbi

rth

wei

ght,

low

birt

hw

eigh

t,pr

eter

mde

liver

y,an

dne

onat

alm

orta

lity

Stud

yP

opul

atio

nSt

udy

desi

gn/g

roup

s

Bir

thw

eigh

tM

ean

(SD

),di

ff(9

5%C

L),

gL

BW

%R

R(9

5%C

L)

Pre

term

birt

h,%

RR

(95%

CL

)

Neo

nata

lm

orta

lity

per

1000

birt

hs,R

R(9

5%C

L)

Com

men

tsR

amak

rish

nan

etal

.200

3(8

3)

Mex

ico,

sem

iurb

anC

ontr

ol:F

e(n

=32

3)M

M(n

=32

2)M

Mve

rsus

cont

rol

2977

(393

)29

81(3

91)

-

8.89

8.49 -

6.54

7.48 -

Not

repo

rted

Acc

epta

ble

nutr

ition

alst

atus

.Low

LB

Wra

tes

Chr

istia

net

al.2

003

(21,

26)

Nep

al,

Sarl

ahi,

rura

l

Con

trol

:VA

(n=

685)

FAFe

:(n

=63

5)M

M(n

=70

5)FA

Feve

rsus

cont

rol

MM

vers

usco

ntro

l

2587

(445

)26

52(4

36)

2659

(446

)37

(−16

,90)

a

64(1

2,11

9)a

43.4

34.3

35.3

0.84

(0.7

2,0.

99)

0.86

(0.7

4,0.

99)

20.4

23.1

20.6

1.13

(0.9

0,1.

40)

1.01

(0.8

2,1.

26)

45.7

36.3

54.0

0.80

(0.5

0,1.

27)

1.19

(0.7

7,1.

83)

Num

ber

for

mor

talit

you

tcom

eis

:876

,772

,&

870

for

cont

rol,

FAFe

&M

M

Friis

etal

.20

04(3

5)H

arar

e,Z

imba

bwe

ante

nata

lcl

inic

s:H

IV-

nega

tive

Con

trol

:PL

(n=

361)

MM

(n=

364)

MM

vers

usP

L

3044

3070

26(−

38,9

1)

9.7

7.1

0.74

(0.4

5,1.

20)

16.2

12.7

0.79

(0.5

5,1.

13)

Not

repo

rted

Wom

enre

ceiv

edir

on-f

olic

acid

;hig

hlo

ssto

follo

w-u

p

Kae

stel

etal

.20

05(5

1)G

uine

a-B

issa

u,an

tena

tal

clin

ics

Con

trol

:FeF

A(n

=36

6)M

Mx1

RD

A(n

=36

0)M

M2x

RD

A(n

=37

4)M

M1

vers

usFe

FAM

M2

vers

usFe

FA

3022

3055

3097

49(−

22,1

21)b

88(1

7,15

9)b

13.6

12.0

10.1

0.88

(0.5

7,1.

37)b

0.70

(0.4

4,1.

11)b

Not

repo

rted

42 50 441.

15(0

.63,

2.10

)b

1.09

(0.6

0,1.

99)b

Bir

thw

eigh

tmis

sing

for

974

infa

nts

Osr

inet

al.

2005

(79)

Nep

al,

Dha

nusa

,ur

ban/

rura

l,an

tena

tal

clin

ics

Con

trol

:FeF

A(n

=52

3)M

M(n

=52

9)M

Mve

rsus

cont

rol

2733

(422

)28

10(5

29)

77(2

4,13

0)

25 190.

69(0

.52,

0.93

)

10 80.

85(0

.57,

1.29

)

20 30.6

1.53

(0.7

2,3.

23)

Num

ber

for

mor

talit

you

tcom

e:56

8an

d57

1fo

rco

ntro

land

MM

Zag

reet

al.

2007

(114

)N

iger

,ru

ral

Con

trol

:FeF

A(n

=12

22)

MM

(n=

1328

)M

Mve

rsus

cont

rol

3025

(205

)30

92(1

90)

67(5

1,82

)

8.4

7.2

−1.2

(−1.

8,−0

.6)e

Not

asse

ssed

/re

port

edN

otas

sess

ed/

repo

rted

92 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


Shan

kar

etal

.200

8(9

9)

Indo

nesi

a,L

ombo

kC

ontr

ol:F

eFA

(n=

15,4

86)

MM

(n=

15,8

04)

MM

vers

usco

ntro

l

3176

3198

21(−

11,5

3)

11 90.

86(0

.73,

1.01

)

Not

asse

ssed

/re

port

ed25

.522

.30.

90(0

.76,

1.06

)

Bir

thw

eigh

tmea

sure

din

asu

bgro

upof

11,1

01;3

-mon

thm

orta

lity

sign

ifica

ntly

redu

ced

by18

%Z

eng

etal

.20

08(1

15)

Chi

na,r

ural

Con

trol

:FA

(n=

1545

)Fe

FA(n

=14

70)

MM

(n=

1406

)Fe

FAve

rsus

cont

rol

MM

vers

usco

ntro

l

3154

(445

)31

74(4

24)

3197

(438

)24

(−10

,59)

c

42(7

,77)

c

5.3

4.5

4.1

0.81

(0.5

9,1.

12)c

0.78

(0.5

6,1.

08)c

6.1

4.9

5.2

0.79

(0.5

8,1.

07)

0.86

(0.6

4,1.

14)

20.2

10.7

12.3

0.53

(0.2

9,0.

97)

0.61

(0.3

4,1.

10)

Impa

ctof

FAFe

sign

ifica

ntfo

rea

rly

pret

erm

Rob

erfr

oid

etal

.200

8(9

2)

Bur

kina

Faso

,rur

alC

ontr

ol:F

eFA

(n=

628)

MM

(n=

632)

MM

vers

usco

ntro

l

2877

(424

)29

14(4

50)

41(−

11,9

4)

15.6

14.6

0.91

(0.6

5,1.

28)d

13.4

14.2

1.04

(0.7

5,1.

45)d

10 192.

1(0

.78,

5.67

)d

Diff

eren

cein

peri

nata

lm

orta

lity

was

mar

gina

llysi

gnifi

cant

Suna

wan

get

al.2

009

(101

)

Wes

tJav

a,In

done

sia

Con

trol

:FeF

A(n

=34

1)M

M(n

=38

4)M

Mve

rsus

cont

rol

3054

(419

)30

94(4

38)

40(−

22,1

03)

6.3

7.3

0.84

(0.4

7,1.

50)

Not

asse

ssed

42 230.

54(0

.20,

1.20

)B

hutt

aet

al.2

009

(11)

Kar

achi

,P

akis

tan,

peri

urba

n

Con

trol

:FeF

A(n

=12

30)

MM

(n=

1148

)M

Mve

rsus

cont

rol

2880

(500

)29

50(6

00)

70

19.6

17.7

NS

Not

repo

rted

23.5

43.2

1.64

(0.9

4,2.

87)

Diff

eren

cein

earl

yne

onat

alm

orta

lity

was

sign

ifica

nt

Low

birt

hw

eigh

t:<

2500

g.P

rete

rmde

liver

y:ge

stat

iona

ldur

atio

nof

<37

wk.

a Adj

uste

dfo

rm

ater

nalw

eigh

tatb

asel

ine.

bA

djus

ted

for

mal

aria

para

site

mia

,ane

mia

,inf

ants

ex,a

ndse

ason

sof

birt

h.c A

djus

ted

for

mul

tiple

birt

hsan

dcl

uste

rra

ndom

izat

ion.

dA

djus

ted

for

mal

aria

prev

entio

nan

dhe

alth

cent

er.

e Abs

olut

edi

ffere

nce.

CL

,con

fiden

celim

its;F

A,f

olic

acid

;Fe,

iron

;MM

,mul

tiple

mic

ronu

trie

nt;P

L,p

lace

bo;R

R,r

elat

ive

risk

;SD

,sta

ndar

dde

viat

ion;

VA

,vita

min

A.


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


Guinea-Bissau that used one and two times theRDA of nutrients in the multiple micronutri-ent supplements compared with iron-folic acidas control showed no impact on birth weightwith the single-RDA formulation (53 g, −19,125); however, supplementation with the for-mulation that provided twice the RDA for eachnutrient increased birth weight by 95 g (25,167 g), although adjustment attenuated this ef-fect (51). No difference in perinatal or neona-tal mortality was observed with the increasedbirth weight, although the study was not largeenough to show differences in this outcome, andthe loss to follow-up was high (51).

One of two double-blind trials in Nepalwas conducted in the southern plains Districtof Sarlahi and compared four combinationsof micronutrients taken from early pregnancythrough three months postpartum to a controlsupplement (21, 26). The test supplements con-tained folic acid alone, folic acid+iron, folicacid+iron+zinc, or a multiple-micronutrientformulation with folic acid+iron+zinc and 11other micronutrients. All supplements also con-tained vitamin A, with vitamin A alone beingthe control. Folic acid supplementation did notincrease birth weight. The combination of iron-folic acid increased mean birth weight and re-duced LBW (RR = 0.84, 95% CI: 0.72, 0.99),but adding zinc antagonized beneficial effectsof iron, and the impact on low birth weightwas attenuated (RR = 0.96). MMS resulted inthe greatest increase in mean birth weight of64 g (95% CI: 12, 115 g). The three-monthinfant mortality rate in this trial was 55.9% inthe control group and, although nonsignificant,was lower by about 20% in the folic acid andfolic acid+iron groups but not in the multiple-micronutrient supplement group (59.8%) (26).Among preterm infants, mortality was loweredsignificantly (by over 40%–60%) with the folicacid and iron-folic acid supplement combina-tions (p < 0.001).

A second randomized trial, conducted alsoin Nepal in the District of Dhanusa but basedout of a clinic, compared the UNIMMAP for-mulation with iron-folic acid and reported a sig-nificant increase in birth weight (77 g, 95% CI:

24–130) due to MMS (79). However, the in-crease in birth size did not result in improvedinfant survival. Data from the two Nepal tri-als were pooled to estimate the impact of MMScompared to iron-folic acid on fetal loss and in-fant mortality that neither study was indepen-dently powered to examine (22). The pooledanalysis of the two Nepal studies showed sig-nificant increases of 36% and 52% in peri-natal and neonatal mortality, respectively, as-sociated with MMS compared with iron-folicacid.

Other trials of MMS in South Asia wereconducted in Bangladesh and Pakistan (11).Although the Bangladesh data remain unpub-lished, both these studies using the UNIMMAPformulation have failed to find an impact ofMMS on low birth weight, and the study inPakistan even showed that the neonatal mor-tality rate was somewhat higher in the MMSgroup compared with the iron-folic acid group(RR = 1.64, 95% CI: 0.94, 2.87) (11).

In a trial in Niger, the UNIMAPP supple-ment increased mean birth weight by 67 g (51,82 g) versus iron-folic acid, although 30% of thedata were missing (114). In Burkina Faso, theUNIMMAP supplement increased both birthweight (52 g, 4, 100 g) and length (3.6 mm, 0.8,6.3 mm), but only after adjustment of gesta-tional age at delivery (92). The risk of perinatalmortality was marginally significantly increasedin this study with the MMS (OR = 1.78, 95%CI: 0.95, 3.32, p = 0.07) and more so in primi-parous women (OR = 3.44, 95% CI: 1.1, 10.7),an increase previously observed in the two stud-ies in Nepal and Pakistan.

In Indonesia, a large trial (called SUMMIT)involving 31,290 pregnant women had find-ings that differed from the other trials of MMS(99). In this trial, there was no impact of MMSon birth weight (21 g, −11, 53 g), LBW rate(11% in the MMS versus 9% in the iron-folicacid group, p > 0.05), or perinatal or neonatalmortality, but early infant mortality (through3 months of age) was reduced by 18% (RR =0.82, 95% CI: 0.70, 0.95). In a second trial, inWest Java, Indonesia, the UNIMMAP supple-ment did not have a significant impact on birth

94 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


weight (3094 g in the MMS versus 3054 g inthe iron-folic acid control, p > 0.05) or neona-tal mortality (101).

Finally, in a trial in China of 5828 pregnantwomen and 4697 live births, women were ran-domized to daily folic acid (control) versus iron-folic acid or MMS. Iron-folic acid supplemen-tation was not associated with an increase inbirth weight (24 g, −10, 59 g) whereas MMSincreased birth weight by 42 g (7, 78 g) (115).On the other hand, iron-folic acid increased thelength of gestation (by 0.23 wk, 0.10, 0.36), asdid MMS (0.19 wk, 0.06, 0.32 wk). Further-more, iron-folic acid, unlike MMS, reducedearly neonatal mortality by 54% (RR = 0.46,95% CI: 0.21, 0.98), although these analyseswere posthoc (115).

Two other studies that used either a moreunconventional supplement formulation or amore selected population group are also worthnoting. One was a double-blind randomizedtrial among HIV-negative women in Tanzania(33). In this study, women received a daily mul-tivitamin supplement (containing multiples ofRDA of vitamins) or a placebo during preg-nancy. The difference in birth weight betweensupplement groups was 67 g (p < 0.001), andthere was a reduction in LBW by 18% (RR =0.82, 95% CI: 0.70, 0.95). There was no impacton preterm birth, but SGA births were signifi-cantly reduced. In another small study done ina clinic in Delhi, India, 200 pregnant womenwith body mass index (BMI) <18.5 kg/m2 orwith hemoglobin 7–9 g/dL were enrolled inlate gestation to receive a supplement contain-ing 29 vitamins and minerals or a placebo (98).A strong treatment effect was observed with anincrement of 98 g (−16, 213 g) in birth weight,which was not significant due to the small sam-ple size. However, the incidence of LBW de-clined by 70% (RR = 0.30, 95% CI: 0.13,0.71) and that of early neonatal morbidity by58% (RR = 0.42, 95% CI: 0.19, 0.94). Theresults from these studies may not be general-izable because they both used unconventionalsupplement formulations, and one of the stud-ies was done in a small select group of high-riskwomen.

Three meta-analyses have now been con-ducted of these trials, although only the mostrecent one includes all of the 12 trials done indeveloping countries discussed above (64). Thefirst one was a systematic Cochrane analysis un-dertaken by Haider & Bhutta (44) of published(n = 6) and at that time unpublished (n = 3)trials of MMS. This analysis compared two ormore nutrients with a placebo, no supplement,or a supplement with a single nutrient. A sub-analysis also compared multiple micronutrientswith iron-folic acid. The main conclusion ofthis review was that the evidence to suggest thatiron-folic acid should be replaced with multiplemicronutrients was lacking and that further re-search was needed to demonstrate either ben-efit or potential adverse effects of a multiplemicronutrient supplement. The second meta-analysis included data from developed countriesand HIV-1 infected populations and found pre-natal MMS to increase birth weight and reduceLBW compared with placebo or iron-folic acidas control (43). There was no evidence of a sig-nificant impact on SGA or preterm birth, andmortality was not examined as an outcome.

In October 2005, UNICEF, WHO, and theUN Standing Committee on Nutrition com-missioned a systematic review team to under-take a meta-analysis of 12 trials conducted indeveloping countries to examine the impact ofantenatal MMS compared with iron-folic acidon birth outcomes and neonatal survival (31,64, 93). The pooled estimates for birth weightand fetal growth outcomes were as follows(Table 2): MMS increased mean birth weight(22.4 g, 95% CI: 8.3 to 36.4; p = 0.002),reduced LBW (OR = 0.89, 95% CI 0.81–0.97; p = 0.01) and SGA birth (OR = 0.90,95% CI 0.82–0.99; p = 0.03), and increasedlarge-for-gestational-age birth (OR = 1.13,95% CI 1.00–1.28; p = 0.04) (31). Therewas no significant impact on birth length, du-ration of gestation, or the risk of preterm.There was also no reduction in stillbirth, peri-natal mortality, or neonatal mortality. Therewas a suggested higher risk of early mortalitywith MMS compared with iron-folic acid, al-though not statistically significant (OR 1.23,


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


Table 2 Results of a meta-analysis of the effects of antenatal multiplemicronutrient supplementation versus iron-folic acid on birth outcomesin 12 randomized controlled trials in developing countries (31, 93)

Birth outcome Pooled effect size (95% CI)Birth weight, g 22.4 (8.3, 36.4)Low birth weight (<2500 g) 0.89 (0.81, 0.97)Small for gestational age 0.90 (0.82, 0.99)Large for gestational age 1.13 (1.00, 1.28)Gestational age, days 0.17 (−0.35, 0.70)Preterm delivery (<37 weeks) 1.00 (0.93, 1.09)Stillbirths 1.01 (0.88, 1.16)Perinatal mortality 1.11 (0.93, 1.33)Early neonatal mortality 1.23 (0.96, 1.59)Late neonatal mortality 0.94 (0.73, 1.23)

95% CI 0.96–1.59) (93). Maternal prepreg-nancy BMI modified the treatment effect; MMSincreased birth weight only among women withhigher BMI (>20 kg/m2). Exclusion of the largeIndonesian study (99), which also found no sig-nificant impact of MMS on perinatal or neona-tal mortality, resulted in a significant increase inearly neonatal mortality in the pooled analysis.Thus, the meta-analysis of the 12 MMS trialsfound a small, modest increase in birth weight,an 11% reduction in low birth weight, but noimpact on neonatal survival. This suggests thatcurrent evidence for replacing antenatal iron-folic acid with a multiple micronutrient supple-ment is weak.

INTERPRETATION OF RESULTS,PLAUSIBLE MECHANISMS, ANDNUTRIENT INTERACTIONS

The findings from the trials described aboveshow equivocal benefits of antenatal multiple-micronutrient supplements, and perhaps itwould be appropriate to raise safety concernsregarding their use for women in the devel-oping world. That such an intervention wassystematically and extensively examined acrossvarious population groups in developing coun-try settings is commendable and provides themuch-needed data on the efficacy and safety of a

one-a-day micronutrient supplement for preg-nant women.

First, it may be useful to examine the appro-priateness of the amount and mix of nutrientsin the formulation—the UNIMMAP—thatwas tested in a majority of the studies. Many ofthese studies tested a multiple micronutrientsupplement compared with the currentlyrecommended iron-folic acid supplementas control. As described previously, beyondiron, there is limited evidence that othermicronutrients are important for enhancingbirth outcomes. Thus, the scientific rationalefor each essential micronutrient added in themix is the theoretical increased need for thesenutrients during pregnancy and the need forcorrecting underlying deficiencies. In settingswhere some micronutrients (such as iron)are more limiting for fetal growth and otheroutcomes, it is important to consider whethernutrient-nutrient synergies or antagonisms arelikely to play a role. Related to this, the negativeinteraction between iron and zinc may be rel-evant to examine, especially in settings whereiron deficiency during pregnancy is commonand limiting. The studies in Nepal and China,for example, in which iron-folic acid was in-dependently assessed, found this combinationto yield better outcomes with regard to birthweight than did the combination with addedzinc (21) or with regard to survival comparedto added multiple micronutrients that includedzinc (21, 115). In two studies that evaluatedmaternal iron and hematologic indicators asoutcomes, MMS did less well compared withiron (alone or with folic acid) (24, 86).

The UNIMMAP supplement contains30 mg of iron, which, although close to the U.S.Institute of Medicine RDA for iron in pregnantwomen (27 mg), is half the amount recom-mended for antenatal supplementation in de-veloping countries (107). The rationale for thelower dosage was that other vitamins in the sup-plement would likely enhance iron metabolism(107). However, data from the above twostudies provided no evidence in support of this.It may be argued that the amount of iron inthe MMS was too low in some settings, such as

96 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


Pakistan, where the rates of severe anemiaduring pregnancy are high (10%) despite theabsence of malaria (23). On the other hand, thestudy in Bangladesh, which compared 30 mgversus 60 mg of iron, recorded no differencein the birth outcomes between these twogroups, but neither did MMS compared witheither of the two iron controls (2). Thus, com-bining nutrients in a supplement may resultin nutrient-nutrient interactions, specificallybetween iron and zinc but also between othernutrients, which are all not well understood,especially since multiple possible combinationsexist across the 14–15 micronutrients, resultingin numerous potential multiway interactions.

The other question that has been posed iswhether a single RDA of these nutrients is suf-ficient to correct the existing micronutrient de-ficiencies, especially when pregnancy providesa narrow window of opportunity during whichto intervene. Only two studies can speak tothis issue for birth outcomes. The studies inGuinea-Bissau (51) and Tanzania (33) used twotimes or multiples of RDAs of nutrients andfound significant effects on birth weight. Thestudy in Guinea-Bissau (51) even showed thatthe same supplement formulation with a sin-gle RDA of nutrients did not increase birthweight. In Nepal, assessment of maternal sta-tus using numerous biochemical indicators re-vealed a significant reduction in deficiencies ofnumerous vitamins and minerals with a singleRDA MMS (20). However, for many nutrients,deficiencies were not corrected fully. Althoughthese data are intriguing, they are insufficient toserve as the basis for policy and program rec-ommendations for a universal supplement con-taining multiples of RDAs for use in developingcountries.

The other puzzling piece is that of the sug-gested increased risk of mortality due to MMSdespite the increase in birth weight, which is ex-pected to translate into beneficial gains in sur-vival. Explanations have so far focused on anupward shift in the entire distribution of birthweight with the MMS and increase in larger ba-bies (53), putting them at an increased risk ofmortality (26). In Nepal, MMS was also found

to increase the risk of birth asphyxia in theneonates (19). Other explanations include in-creased uterine sensitivity to oxytocin (22). Incontrast to MMS, iron supplementation as ex-amined in one study only increased birth weightin the left tail of the distribution and did not re-sult in an increased risk of neonatal morbidityor mortality (19, 53).

The recent meta-analysis of the 12 trialsshowing significant increase in large-for-gestational-age babies due to MMS versusiron-folic acid (31) corroborates the earlyNepal study findings of increased high birth-weight babies (21). The meta-analysis alsofound a significant interaction between MMSand maternal BMI; MMS increased birthweight largely among women with a highBMI (31). This suggests that the action of mi-cronutrients may require utilization of energyand protein as substrates. In fact, B-complexvitamins—specifically riboflavin, niacin, andthiamin—each play a major role in energy, fat,and protein metabolism. The major forms ofniacin are the cellular pyridine nucleotides.NAD-dependent enzymes are involved inβ-oxidation of fatty acyl coA, oxidation of ke-tone bodies and degradation of carbohydrate,and catabolism of amino acids. Riboflavin isessential for the synthesis of coenzymes thatfunction in oxidation-reduction reactions in-volved in the catabolism of glucose, fatty acids,ketone bodies, and amino acids. Flavoenzymesparticipate in numerous pathways of energyproduction via the respiratory chain, whereasthiamin coenzyme (TPP) functions in primeinterconversions of sugar phosphates and in de-carboxylation reactions with energy productionfrom α-keto acids. Thus, supplementation withthese vitamins during pregnancy may perhapshave enhanced or increased efficiency of energyutilization and availability for fetal growth,especially among women with higher BMI.

On the other hand, vitamins B-12 and B-6 are more like folic acid in their biochemi-cal activity as 1-C units in a variety of reac-tions; therefore, also like folic acid, they maynot be associated with increases in birth weight.However, the biology of the differential effect


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


observed with multiple micronutrients needsfurther investigation. Recently, a study in ruralBurkina Faso examined the impact of a MMSalone versus a food supplement fortified withmultiple micronutrients (48). After adjustingfor gestational age, the fortified food supple-ment had a significant impact on birth lengthcompared with MMS alone, although the ef-fect on birth weight was modest (31 g) and notsignificant.

It would be important also to re-examine thepreviously assumed strong linear inverse rela-tionship between birth weight and infant mor-tality. Birth weight may be a proxy measure ofinfant health, and when used as a main out-come measure in trials, was only modestly en-hanced with MMS, an increase that paradox-ically conferred no survival advantage. It hasbeen questioned whether absolute changes inbirth weight are important for altering survival(78). For example, preterm birth or FGR mayhave a direct effect on mortality without birthweight being in the causal pathway. Betweenpreterm birth and fetal growth restriction, thetwo main biologic factors leading to low birthweight, preterm has a stronger association withinfant mortality than FGR (18). The MMSstudies found no impact on preterm birth orduration of gestation. On the other hand, iron-folic acid in three trials was found to increasegestational age of pregnancy or reduce preterm(27, 100, 115). These relationships need furtherscrutiny, and studies testing nutritional inter-ventions need to examine both components ofbirth weight as well as outcomes directly mea-suring fetal health, such as perinatal and neona-tal mortality.

SUMMARY AND CONCLUSION

Maternal micronutrient deficiencies arewidespread, and their prevention is important.

However, most approaches to address thesedeficiencies have focused largely on the narrowperiod during pregnancy, primarily for thepotential for these micronutrients to enhancebirth outcomes. It is unlikely that supple-mentation or other approaches limited to thepregnancy period would eliminate micronutri-ent deficiencies that stem from chronic dietaryinadequacies. Thus, it is crucial that any policyof antenatal multiple micronutrient strategyis grounded in scientific evidence of efficacy(benefit with respect to a range of healthoutcomes) and safety (posing minimal risk forall major outcomes). Current evidence suggeststhat multiple micronutrients may contributeonly modestly to improvements in birth weightand have no impact on gestational length orfetal or neonatal survival. Thus, evidence todate does not indicate the widespread use ofmultiple micronutrients during pregnancy.Conversely, there seems to be strong evidencethat the existing policy for antenatal iron-folicacid use is sound, as new evidence has revealedthe beneficial impact of iron supplementationon outcomes beyond birth weight, such asneonatal and child survival. What is neededis urgent energizing of the failing antenatalcare programs and delivery of iron-folicacid to pregnant women in many low- andmiddle-income countries.

Finally, data on the burden of maternal mi-cronutrient deficiencies beyond iron, vitaminA, and zinc is limited. Thus, the prevalenceand severity of concurrent maternal micronu-trient deficiencies needs to be estimated us-ing broadly representative populations in eachhigh-risk region of the world. Furthermore, in-creasing evidence suggests that pre- and peri-conceptional maternal micronutrient nutriturecan influence fetal and infant health (15); thismerits further discussion for a critical researchstrategy.

DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that mightbe perceived as affecting the objectivity of this review.

98 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


ACKNOWLEDGMENTS

The author thanks Alison Gernand for contributing to the section on mechanisms related tonutrient transfer and placental factors influencing fetal growth.

LITERATURE CITED

1. Ahmed A, Perkins J. 2000. Angiogenesis and intrauterine growth restriction. Baillieres Best Pract. Res.Clin. Obstet. Gynaecol. 14:981–98

2. Alam DS. 2009. Prevention of low birth weight. In Nestle Nutrition Institute Workshop Series PediatricProgram, Vol. 63. Emerging Societies-–Coexistence of Childhood Malnutrition and Obesity, ed. SC Kalhan,AM Prentice, CS Yajnik, pp. 209–25. Basel: Karger

3. Allen LH. 2001. Biological mechanisms that might underlie iron’s effects on fetal growth and pretermbirth. J. Nutr. 131:581–89S

4. Alsat E, Guibourdenche J, Couturier A, Evain-Brion D. 1998. Physiological role of human placentalgrowth hormone. Mol. Cell. Endocrinol. 140:121–27

5. Barker DJ. 2006. Adult consequences of fetal growth restriction. Clin. Obstet. Gynecol. 49:270–836. Bassett NS, Oliver MH, Breier BH, Gluckman PD. 1990. The effect of maternal starvation on plasma

insulin-like growth factor I concentrations in the late gestation ovine fetus. Pediatr. Res. 27:401–47. Bauman DE, Currie WB. 1980. Partitioning of nutrients during pregnancy and lactation: a review of

mechanisms involving homeostasis and homeorhesis. J. Dairy Sci. 63:1514–298. Beitens IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. 1973. The metabolic clearance rate, blood

production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term.Pediatr. Res. 7:509–519

9. Benediktsson R, Calder AA, Edwards CR, Seckl JR. 1997. Placental 11 beta-hydroxysteroid dehydroge-nase: a key regulator of fetal glucocorticoid exposure. Clin. Endocrinol. (Oxf.) 46:161–66

10. Bernstein IM, Ziegler W, Badger GJ. 2001. Plasma volume expansion in early pregnancy. Obstet. Gynecol.97:669–72

11. Bhutta ZA, Rizvi E, Raza S, Hotwani S, Zaidi S, et al. 2009. A comparative evaluation of multiplemicronutrient and iron-folic acid supplementation during pregnancy in Pakistan: impact on pregnancyoutcomes. Food Nutr. Bull. 40:S496–505

12. Black RE. 2001. Micronutrients in pregnancy. Br. J. Nutr. 85(Suppl. 2):S193–9713. Bonds DR, Mwape B, Kumar S, Gabbe SG. 1984. Human fetal weight and placental weight growth

curves. A mathematical analysis from a population at sea level. Biol. Neonate 45:261–7414. Caulfield LE, Zavaleta N, Figueroa A. 1999. Adding zinc to prenatal iron and folate supplements improves

maternal and neonatal zinc status in a Peruvian population. Am. J. Clin. Nutr. 69:1257–6315. Cetin I, Berti C, Calabrese S. 2009. Role of micronutrients in the periconceptional period. Hum. Reprod.

Update. doi:10.1093/humupd/dmp02516. Chellakooty M, Vangsgaard K, Larsen T, Scheike T, Falck-Larsen J, et al. 2004. A longitudinal study of

intrauterine growth and the placental growth hormone (GH)-insulin-like growth factor I axis in maternalcirculation: association between placental GH and fetal growth. J. Clin. Endocrinol. Metab. 89:384–91

17. Cheng Y, Dibley MJ, Zhang X, Zeng L, Yan H. 2009. Assessment of dietary intake among pregnantwomen in a rural area of western China. BMC Public Health. doi: 10.1186/1471-2458-9-222

18. Christian P. 2008. Infant mortality. In Nutrition and Health in Developing Countries, ed. RD Semba, MWBloem, pp. 87–111. Totowa, NJ: Humana

19. Christian P, Darmstadt GL, Wu L, Khatry SK, LeClerq SC, et al. 2008. The impact of maternalmicronutrient supplementation on early neonatal morbidity in rural Nepal: a randomized, controlledcommunity trial. Arch. Dis. Child. 93:660–64

20. Christian P, Jiang T, Khatry SK, LeClerq SC, Shrestha SR, West KP Jr. 2006. Antenatal micronutrientsupplementation and biochemical indicators of status and subclinical infection in rural Nepal. Am. J.Clin. Nutr. 83:788–94


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


21. Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq SC, et al. 2003. Effects of alternative maternalmicronutrient supplements on low birth weight in rural Nepal: double blind randomised communitytrial. BMJ 326:571–76

22. Christian P, Osrin D, Manandhar DS, Khatry SK, de L Costello AM, West KP Jr. 2005. Antenatalmicronutrient supplements in Nepal (letter). Lancet 366:711–12

23. Christian P, Shahid F, Rizvi A, Klemm RDW, Bhutta ZA. 2009. Treatment response to standard of carefor severe anemia in pregnant women and effect of multivitamins and enhanced anthelminthics. Am. J.Clin. Nutr. 89:853–61

24. Christian P, Shrestha JB, LeClerq SC, Khatry SK, Jiang T, et al. 2003. Supplementation with micronu-trients in addition to iron and folic acid does not further improve the hematologic status of pregnantwomen in rural Nepal. J. Nutr. 133:3492–98

25. Christian P, Stewart CP, LeClerq SC, Wu L, Katz J, et al. 2009. Antenatal and postnatal iron supple-mentation and childhood mortality in rural Nepal: a prospective follow-up in a randomized controlledcommunity trial. Am. J. Epidemiol. 170:1127–36

26. Christian P, West KP, Khatry SK, LeClerq SC, Pradhan EK, et al. 2003. Effects of maternal micronu-trient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal. Am. J.Clin. Nutr. 78:1194–202

27. Cogswell ME, Parvanta I, Ickes L, Yip R, Brittenham GM. 2003. Iron supplementation during pregnancy,anemia, and birth weight: a randomized controlled trial. Am. J. Clin. Nutr. 78:773–81

28. Costello de L AM, Osrin D. 2003. Micronutrient status during pregnancy and outcomes for newborninfants in developing countries. J. Nutr. 133:1757–64S

29. Cunningham GF, Gant NF, Loveno KJ, Gilstrap LC, Hauth JC, Wenstrom KD. 2001. Williams Ob-stetrics. New York: McGraw-Hill. 21st ed.

30. Dreyfuss ML, West KP Jr, Katz J, LeClerq SC, Pradhan EK, et al. 1997. Effects of maternal vitaminA or beta-carotene on intrauterine/neonatal and early infant growth in Nepal. In Report of the XVIIIInternational Vitamin A Consultative Group Meeting, Cairo, Egypt. ILSI Res. Found., Washington, DC(Abstr.)

31. Fall CHD, Fisher D, Clive O, Barrie M, Maternal Micronutr. Suppl. Study Group. 2009. Multiplemicronutrient supplementation during pregnancy in low-income countries: a meta-analysis of effects onbirth size and gestation length. Food Nutr. Bull. 40:S533–46

32. Fall CH, Yajnik CS, Rao S, Davies AA, Brown N, Farrant HJ. 2003. Micronutrients and fetal growth.J. Nutr. 133:1747–56S

33. Fawzi WW, Msamanga GI, Urassa W, Hertzmark E, Petraro P, et al. 2007. Vitamins and perinataloutcomes among HIV-negative women in Tanzania. N. Engl. J. Med. 356:1423–31

34. Fowden AL, Sibley C, Reik W, Constancia M. 2006. Imprinted genes, placental development and fetalgrowth. Horm. Res. 65(Suppl. 3):50–58

35. Friis H, Gomo E, Nyazema N, Ndhlovu P, Krarup H, et al. 2004. Effect of multimicronutrient supple-mentation on gestational length and birth size: a randomized, placebo-controlled, double-blind effec-tiveness trial in Zimbabwe. Am. J. Clin. Nutr. 80:178–84

36. Fuglsang J, Ovesen P. 2006. Aspects of placental growth hormone physiology. Growth Horm. IGF Res.16:67–85

37. Garcia-Guerra A, Neufeld LM, Hernandez-Cordero S, Rivera J, Martorell R, Ramakrishnan U. 2009.Prenatal multiple micronutrient supplementation impact on biochemical indicators during pregnancyand postpartum. Salud Publica Mex. 51:327–35

38. Gardosi J. 2005. Fetal growth: towards an international standard. Ultrasound Obstet. Gynecol. 26:112–1439. Gluckman PD, Cutfield W, Harding JE, Milner D, Jensen E, et al. 1996. Metabolic consequences of

intrauterine growth retardation. Acta Paediatr. Suppl. 417:3–640. Gluckman PD, Hanson MA. 2007. Developmental plasticity and human disease: research directions.

J. Intern. Med. 261:461–7141. Gluckman PD, Pinal CS. 2003. Regulation of fetal growth by the somatotrophic axis. J. Nutr. 133:1741–

46S

100 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


42. Goland RS, Tropper PJ, Warren WB, Stark RI, Jozak SM, Conwell IM. 1995. Concentrations ofcorticotrophin-releasing hormone in the umbilical-cord blood of pregnancies complicated by pre-eclampsia. Reprod. Fertil. Dev. 7:1227–30

43. Gupta P, Ray M, Dua T, Radhakrishnan G, Kumar R, Sachdev HP. 2007. Multimicronutrient supple-mentation for undernourished pregnant women and the birth size of their offspring: a double-blind,randomized, placebo-controlled trial. Arch. Pediatr. Adolesc. Med. 161:58–64

44. Haider BA, Bhutta ZA. 2007. Multiple-micronutrient supplementation for women during pregnancy.Cochrane Database Syst. Rev. 4:CD004905

45. Harding JE. 2001. The nutritional basis of the fetal origins of adult disease. Int. J. Epidemiol. 30:15–2346. Hemminki E, Starfield B. 1978. Routine administration of iron and vitamins during pregnancy: review

of controlled clinical trials. Br. J. Obstet. Gynaecol. 85:404–1047. Hess SY, King JC. 2009. Effects of maternal zinc supplementation on pregnancy and lactation outcomes.

Food Nutr. Bull. 30:S60–7848. Huybregts L, Roberfroid D, Lanou H, Menten J, Meda N, et al. 2009. Prenatal food supplementation

fortified with multiple micronutrients increases birth length: a randomized controlled trial in ruralBurkina Faso. Am. J. Clin. Nutr. doi:10.3945/ajcn.2009.28253

49. Hytten F. 1985. Blood volume changes in normal pregnancy. Clin. Haematol. 14:601–1250. Jiang T, Christian P, Khatry SK, Wu L, West KP Jr. 2005. Micronutrient deficiencies in early pregnancy

are common, concurrent, and vary by season among rural Nepali pregnant women. J. Nutr. 135:1106–1251. Kaestel P, Michaelsen KF, Aaby P, Friis H. 2005. Effects of prenatal micronutrient supplements on

birth weight and perinatal mortality: a randomised controlled trial in Guineau Bissau. Eur. J. Clin. Nutr.59:1081–89

52. Karteris E, Vatish M, Hillhouse EW, Grammatopoulos DK. 2005. Preeclampsia is associatedwith impaired regulation of the placental nitric oxide-cyclic guanosine monophosphate pathway bycorticotropin-releasing hormone (CRH) and CRH-related peptides. J. Clin. Endocrinol. Metab. 90:3680–87

53. Katz J, Christian P, Dominici F, Zeger SL. 2006. Treatment effects of maternal micronutrient supple-mentation vary by percentiles of the birth weight distribution in rural Nepal. J. Nutr. 136:1389–94

54. Katz J, West KP Jr, Khatry SK, Pradhan EK, LeClerq SC, et al. 2000. Low dose vitamin A or beta-carotene supplementation does not reduce early infant mortality: a double-masked, randomized, con-trolled, community trial in Nepal. Am. J. Clin. Nutr. 71:1570–76

55. Kiely M, Cogan PF, Kearney PJ, Morrissey PA. 1999. Concentrations of tocopherols and carotenoidsin maternal and cord blood plasma. Eur. J. Clin. Nutr. 53:711–15

56. Kinare AS, Natekar AS, Chinchwadkar MC, Yajnik CS, Coyaji KJ, et al. 2000. Low midpregnancyplacental volume in rural Indian women: a cause for low birth weight? Am. J. Obstet. Gynecol. 182:443–48

57. King JC. 2000. Physiology of pregnancy and nutrient metabolism. Am. J. Clin. Nutr. 71:1218–25S58. Kovacs CS. 2008. Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from

human and animal studies. Am. J. Clin. Nutr. 88:520–28S59. Kramer MS. 1987. Intrauterine growth and gestational duration determinants. Pediatrics 80:502–1160. Kramer MS. 2003. The epidemiology of adverse pregnancy outcomes: an overview. J. Nutr. 133:1592–

96S61. Kramer MS, Kukuma R. 2003. Energy and protein intake in pregnancy. Cochrane Database Syst. Rev.

4:CD00003262. Lindblad B, Zaman S, Malik A, Martin H, Ekstrom AM, et al. 2005. Folate, vitamin B12, and homocys-

teine levels in South Asian women with growth-retarded fetuses. Acta Obstet. Gynecol. Scand. 84:1055–6163. Mahomed K, Bhutta Z, Middleton P. 2007. Zinc supplementation for improving pregnancy and infant

outcome. Cochrane Database Syst. Rev. CD00023064. Margetts BM, Fall CHD, Ronsmans C, Allen LH, Fisher DJ, Matern. Micronutr. Suppl. Study Group.

2009. Multiple micronutrient supplementation during pregnancy in low income countries: review ofmethods and study characteristics for studies included in meta-analysis. Food Nutr. Bull. 40:S506–16

65. McIntire DD, Bloom SL, Casey BM, Leveno KJ. 1999. Birth weight in relation to morbidity and mortalityamong newborn infants. N. Engl. J. Med. 340:1234–38


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


66. McIntyre HD, Serek R, Crane DI, Veveris-Lowe T, Parry A, et al. 2000. Placental growth hormone(GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabeticpregnancies: correlations with fetal growth. J. Clin. Endocrinol. Metab. 85:1143–50

67. McTernan CL, Draper N, Nicholson H, Chalder SM, Driver P, et al. 2001. Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterinegrowth restriction: an analysis of possible mechanisms. J. Clin. Endocrinol. Metab. 86:4979–83

68. Merialdi M, Carroli G, Villar J, Abalos E, Gulmezoglu AM, et al. 2003. Nutritional interventionsduring pregnancy for the prevention or treatment of impaired fetal growth: an overview of randomizedcontrolled trials. J. Nutr. 133:1626–31S

69. Mikkelsen TB, Osler M, Orozova-Bekkevold I, Knudsen VK, Olsen SF. 2006. Association between fruitand vegetable consumption and birth weight: a prospective study among 43585 Danish women. Scand.J. Public Health 34:616–22

70. Mirlesse V, Frankenne F, Alsat E, Poncelet M, Hennen G, Evain-Brion D. 1993. Placental growthhormone levels in normal pregnancy and in pregnancies with intrauterine growth retardation. Pediatr.Res. 34:439–42

71. Mishra V, Thapa S, Retherford RD, Dai X. 2005. Effect of iron supplementation during pregnancy onbirthweight: evidence from Zimbabwe. Food Nutr. Bull. 26:338–47

72. Murphy BE, Clark SJ, Donald IR, Pinsky M, Vedady D. 1974. Conversion of maternal cortisol tocortisone during placental transfer to the human fetus. Am. J. Obstet. Gynecol. 118:538–41

73. Murphy VE, Smith R, Giles WB, Clifton VL. 2006. Endocrine regulation of human fetal growth: therole of the mother, placenta, and fetus. Endocr. Rev. 27:141–69

74. Navarro J, Causse MB, Desquilbet N, Herve F, Lallemand D. 1984. The vitamin status of low birthweight infants and their mothers. J. Pediatr. Gastroenterol. Nutr. 3:744–48

75. Oliver MH, Harding JE, Breier BH, Evans PC, Gluckman PD. 1993. Glucose but not a mixed aminoacid infusion regulates plasma insulin-like growth factor-I concentrations in fetal sheep. Pediatr. Res.34:62–65

76. Ong S, Lash G, Baker PN. 2000. Angiogenesis and placental growth in normal and compromisedpregnancies. Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 14:969–80

77. Osendarp SJ, West CE, Black RE, Maternal Zinc Suppl. Study Group. 2003. The need for maternalzinc supplementation in developing countries: an unresolved issue. J. Nutr. 133:817–27S

78. Osrin D, Costello de L AM. 2000. Maternal nutrition and fetal growth: practical issues in internationalhealth. Semin. Neonatol. 5:209–19

79. Osrin D, Vaidya A, Shrestha Y, Baniya RB, Manandhar DS, et al. 2005. Effects of antenatal multiplemicronutrient supplementation on birthweight and gestational duration in Nepal: double-blind, ran-domized controlled trial. Lancet 365:955–56

80. Pathak P, Kapil U, Kapoor KS, Saxena R, Kumar A, et al. 2004. Prevalence of multiple micronutrientdeficiencies against pregnant women in a rural area of Haryana. Ind. J. Pediatr. 71:1007–14

81. Pena-Rosas JP, Viteri FE. 2009. Effects and safety of preventive oral iron or iron+folic acid supplemen-tation for women during pregnancy (review). Cochrane Database Syst. Rev. 4:CD004736

82. Prentice A, Jarjou LM, Goldberg GR, Bennett J, Cole TJ, Schoenmakers I. 2009. Maternal plasma25-hydroxyvitamin D concentration and birthweight, growth and bone mineral accretion of Gambianinfants. Acta Paediatr. 98:1360–62

83. Ramakrishnan U, Gonzalez-Cossio T, Neufeld LM, Rivera J, Martorell R. 2003. Multiple micronu-trient supplementation during pregnancy does not lead to greater infant birth size than does iron-onlysupplementation: a randomized controlled trial in a semirural community in Mexico. Am. J. Clin. Nutr.77:720–25

84. Ramakrishnan U, Gonzalez-Cossio T, Neufeld LM, Rivera J, Martorell R. 2005. Effect of prenatalmultiple micronutrient supplements on maternal weight and skinfold changes: a randomized double-blind clinical trial in Mexico. Food Nutr. Bull. 26:273–80

85. Ramakrishnan U, Manjrekar R, Rivera J. Gonales-Cossio T, Martorell R. 1999. Micronutrients andpregnancy outcome: a review of the literature. Nutr. Res. 19:103–59

102 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


86. Ramakrishnan U, Neufeld LM, Gonzalez-Cossıo T, Villalpando S, Garcıa-Guerra A, et al. 2004. Multi-ple micronutrient supplements during pregnancy do not reduce anemia or improve iron status comparedto iron-only supplements in semirural Mexico. J. Nutr. 134:898–903

87. Rao S, Yajnik CS, Kanade A, Fall CH, Margetts BM, et al. 2001. Intake of micronutrient-rich foods inrural Indian mothers is associated with the size of their babies at birth: Pune maternal nutrition study.J. Nutr. 131:1217–24

88. Redmer DA, Wallace JM, Reynolds LP. 2004. Effect of nutrient intake during pregnancy on fetal andplacental growth and vascular development. Domest. Anim. Endocrinol. 27:199–217

89. Reik W, Constancia M, Fowden A, Anderson N, Dean W, et al. 2003. Regulation of supply and demandfor maternal nutrients in mammals by imprinted genes. J. Physiol. 547:35–44

90. Reynolds LP, Caton JS, Redmer DA, Grazul-Bilska AT, Vonnahme KA, et al. 2006. Evidence for alteredplacental blood flow and vascularity in compromised pregnancies. J. Physiol. 572:51–58

91. Reynolds LP, Redmer DA. 2001. Angiogenesis in the placenta. Biol. Reprod. 64:1033–4092. Roberfroid D, Huybregts L, Lanou H, Henry MC, Meda N, et al. 2008. Effects of maternal multiple

micronutrient supplementation on fetal growth: a double-blind randomized controlled trial in ruralBurkina Faso. Am. J. Clin. Nutr. 88:1330–40

93. Ronsmans C, Fisher D, Osmond C, Margetts BM, Fall CHD. 2009. Effect of multiple micronutrientsupplementation during pregnancy on stillbirths and early and later neonatal mortality: a meta-analysis.Food Nutr. Bull. 40:S547–55

94. Rosso P. 1981. Nutrition and maternal-fetal exchange. Am. J. Clin. Nutr. 34:744–5595. Rosso P, Donoso E, Braun S, Espinoza R, Salas SP. 1992. Hemodynamic changes in underweight

pregnant women. Obstet. Gynecol. 79:908–1296. Salas SP, Marshall G, Gutierrez BL, Rosso P. 2006. Time course of maternal plasma volume and

hormonal changes in women with preeclampsia or fetal growth restriction. Hypertension 47:203–897. Salas SP, Rosso P, Espinoza R, Robert JA, Valdes G, Donoso E. 1993. Maternal plasma volume expansion

and hormonal changes in women with idiopathic fetal growth retardation. Obstet. Gynecol. 81:1029–3398. Shah PS, Ohlsson A. 2009. Effects of prenatal multimicronutrient supplementation on pregnancy out-

comes: a meta-analysis. CMAJ 180:E99–10899. Shankar AH, Jahari AB, Sebayang SK, Aditiawarman, Apriatni M, et al. 2008. Effect of maternal mul-

tiple micronutrient supplementation on fetal loss and infant death in Indonesia: a double-blind cluster-randomised trial. Lancet 371:215–27

100. Siega-Riz AM, Hartzema AG, Turnbull C, Thorp J, McDonald T, Cogswell ME. 2006. The effectsof prophylactic iron given in prenatal supplements on iron status and birth outcomes: a randomizedcontrolled trial. Am. J. Obstet. Gynecol. 194:512–19

101. Sunawang, Budi Utomo, Adi Hidayat, Kusharisupeni, Subarkah. 2009. Preventing low birth weightthrough maternal multiple micronutrient supplementation: a cluster-randomized controlled trial in In-dramayu, West Java. Food Nutr. Bull. 40:S488–95

102. Thame M, Osmond C, Bennett F, Wilks R, Forrester T. 2004. Fetal growth is directly related to maternalanthropometry and placental volume. Eur. J. Clin. Nutr. 58:894–900

103. Thame M, Osmond C, Wilks R, Bennett FI, Forrester TE. 2001. Second-trimester placental volumeand infant size at birth. Obstet. Gynecol. 98:279–83

104. Thissen JP, Ketelslegers JM, Underwood LE. 1994. Nutritional regulation of the insulin-like growthfactors. Endocr. Rev. 15:80–101

105. Tremblay J, Hardy DB, Pereira LE, Yang K. 1999. Retinoic acid stimulates the expression of 11beta-hydroxysteroid dehydrogenase type 2 in human choriocarcinoma JEG-3 cells. Biol. Reprod. 60:541–45

106. United Nations Children’s Fund, World Health Org. 2004. Low Birthweight: Country, Regional and GlobalEstimates. Geneva: WHO

107. United Nations Children’s Fund, World Health Org., United Nations Univ. 1999. Composition of aMulti-Micronutrient Supplement to be Used in Pilot Programmes Among Pregnant Women in DevelopingCountries. New York: UNICEF

108. Valensise H, Andreoli A, Lello S, Magnani F, Romanini C, De LA. 2000. Multifrequency bioelectricalimpedance analysis in women with a normal and hypertensive pregnancy. Am. J. Clin. Nutr. 72:780–83


Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


109. Villar J, Belizan JM. 1982. The timing factor in the pathophysiology of the intrauterine growth retarda-tion syndrome. Obstet. Gynecol. Surv. 37:499–506

110. Waterland RA, Jirtle RL. 2004. Early nutrition, epigenetic changes at transposons and imprinted genes,and enhanced susceptibility to adult chronic diseases. Nutrition 20:63–68

111. West KP Jr. 2002. Extent of vitamin A deficiency among preschool children and women of reproductiveage. J. Nutr. 132(Suppl.):2857–66S

112. Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE. 2004. Maternal nutrition and fetal develop-ment. J. Nutr. 134:2169–72

113. Wu G, Pond WG, Flynn SP, Ott TL, Bazer FW. 1998. Maternal dietary protein deficiency decreasesnitric oxide synthase and ornithine decarboxylase activities in placenta and endometrium of pigs duringearly gestation. J. Nutr. 128:2395–402

114. Zagre NM, Desplats G, Adou P, Mamadoultaibou A, Aguayo VM. 2007. Prenatal multiple micronutrientsupplementation has greater impact on birthweight than supplementation with iron and folic acid: acluster randomised, double-blind, controlled programmatic study in rural Niger. Food Nutr. Bull. 28:317–27

115. Zeng L, Dibley MJ, Cheng Y, Dang S, Chang S, et al. 2008. Impact of micronutrient supplementationduring pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China:double blind cluster randomised controlled trial. BMJ 337:a2001

104 Christian

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.


61.1

39.8

0.7

11.1

28.3

40.3

31.8

37.4

32.8

13.9

40.2

0

20

40

60

%

Figure 1Prevalence of micronutrient deficiencies during the first trimester among pregnant women in Nepal (50).

www.annualreviews.org • Micronutrients, Birth Weight, and Survival C-1

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.

AR419-FM ARI 22 June 2010 0:50

Annual Review ofNutrition

Volume 30, 2010Contents

The Advent of Home Parenteral Nutrition SupportMaurice E. Shils � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

The Effect of Exercise and Nutrition on Intramuscular Fat Metabolismand Insulin SensitivityChristopher S. Shaw, Juliette Clark, and Anton J.M. Wagenmakers � � � � � � � � � � � � � � � � � � � � � �13

Colors with Functions: Elucidating the Biochemical and MolecularBasis of Carotenoid MetabolismJohannes von Lintig � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �35

Compartmentalization of Mammalian Folate-Mediated One-CarbonMetabolismAnne S. Tibbetts and Dean R. Appling � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �57

Micronutrients, Birth Weight, and SurvivalParul Christian � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �83

Iron Homeostasis and the Inflammatory ResponseMarianne Wessling-Resnick � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 105

Iron, Lead, and Children’s Behavior and CognitionKatarzyna Kordas � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 123

Iron-Sensing Proteins that Regulate Hepcidin and Enteric IronAbsorptionMitchell D. Knutson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 149

Targeting Inflammation-Induced Obesity and Metabolic Diseases byCurcumin and Other NutraceuticalsBharat B. Aggarwal � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 173

Between Death and Survival: Retinoic Acid in Regulation of ApoptosisNoa Noy � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 201

Central Nervous System Nutrient Signaling: The Regulation ofEnergy Balance and the Future of Dietary TherapiesM.A. Stefater and R.J. Seeley � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 219

Fatty Acid Supply to the Human FetusPaul Haggarty � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 237

v

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.

AR419-FM ARI 22 June 2010 0:50

Lipins: Multifunctional Lipid Metabolism ProteinsLauren S. Csaki and Karen Reue � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 257

The Role of Muscle Insulin Resistance in the Pathogenesis ofAtherogenic Dyslipidemia and Nonalcoholic Fatty Liver DiseaseAssociated with the Metabolic SyndromeFrancois R. Jornayvaz, Varman T. Samuel, and Gerald I. Shulman � � � � � � � � � � � � � � � � � � � � 273

Evolutionary Adaptations to Dietary ChangesF. Luca, G.H. Perry, and A. Di Rienzo � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 291

Nutrition, Epigenetics, and Developmental Plasticity: Implications forUnderstanding Human DiseaseGraham C. Burdge and Karen A. Lillycrop � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 315

Physiological Insights Gained from Gene Expression Analysis inObesity and DiabetesMark P. Keller and Alan D. Attie � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 341

The Effect of Nutrition on Blood PressureVincenzo Savica, Guido Bellinghieri, and Joel D. Kopple � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 365

Pica in Pregnancy: New Ideas About an Old ConditionSera L. Young � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 403

The Endocannabinoid System and Its Relevance for NutritionMauro Maccarrone, Valeria Gasperi, Maria Valeria Catani, Thi Ai Diep,

Enrico Dainese, Harald S. Hansen, and Luciana Avigliano � � � � � � � � � � � � � � � � � � � � � � � � � � � � 423

Proline Metabolism and Microenvironmental StressJames M. Phang, Wei Liu, and Olga Zabirnyk � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 441

Indexes

Cumulative Index of Contributing Authors, Volumes 26–30 � � � � � � � � � � � � � � � � � � � � � � � � � � � 465

Cumulative Index of Chapter Titles, Volumes 26–30 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 468

Errata

An online log of corrections to Annual Review of Nutrition articles may be found athttp://nutr.annualreviews.org/errata.shtml

vi Contents

Ann

u. R

ev. N

utr.

201

0.30

:83-

104.

Dow

nloa

ded

from

ww

w.a

nnua

lrev

iew

s.or

gby

Roy

al M

elbo

urne

Ins

titut

e of

Tec

hnol

ogy

(RM

IT)

on 0

9/19

/13.

For

per

sona

l use

onl

y.

Micronutrients, Birth Weight, and Survival

Documents

Transcript of Micronutrients, Birth Weight, and Survival